Margot M Bartelings

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (83)263.51 Total impact

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    ABSTRACT: Background The clinical course of bicuspid aortic valves (BAVs) is variable. Data on predictors of aortopathy and valvular dysfunction mainly focus on valve morphology. Aim To determine whether the presence and extent of the raphe (fusion site of valve leaflets) is associated with the degree of aortopathy and valvular dysfunction in patients with isolated BAV and associated aortic coarctation (CoA). Methods Valve morphology and aortic dimensions of 255 BAV patients were evaluated retrospectively by echocardiography. Results BAVs with a complete raphe had a significantly higher prevalence of valve dysfunction (especially aortic regurgitation) than BAVs with incomplete raphes (82.9 vs. 66.7 %, p = 0.01). Type 1A BAVs (fusion of right and left coronary leaflets) and complete raphe had larger aortic sinus diameters compared with the rest of the population (37.74 vs. 36.01, p = 0.031). Patients with CoA and type 1A BAV had significantly less valve regurgitation (13.6 vs. 55.8 %, p < 0.001) and smaller diameters of the ascending aorta (33.7 vs. 37.8 mm, p < 0.001) and aortic arch (25.8 vs. 30.2 mm, p < 0.001) than patients with isolated BAV. Conclusions Type 1A BAV with complete raphe is associated with more aortic regurgitation and root dilatation. The majority of CoA patients have incomplete raphes, associated with smaller aortic root diameters and less valve regurgitation.
    No preview · Article · Jan 2016 · Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
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    ABSTRACT: Atrioventricular septal defect (AVSD) covers a spectrum of heart anomalies with a common atrioventricular connection and has an incidence of 4-5.3 per 10.000 live births. About half of the AVSDs occur in patient with Down syndrome. This review provides a bench to bedside overview of AVSD. Developmental aspects, nomenclature, anatomy, and classification of AVSD are discussed. Furthermore an overview of genetic and maternal risk factors for AVSD is provided, and available literature on (fetal) diagnosis, surgical techniques and follow-up is presented. Special attention is given to differences in developmental, anatomical and prognostic factors of AVSD between non-syndromic and Down syndrome patients.
    Full-text · Article · Sep 2015 · International journal of cardiology

  • No preview · Article · Sep 2015 · Ultrasound in Obstetrics and Gynecology
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    ABSTRACT: Congenital heart disease is present in 44-56% of fetuses with Down syndrome (DS). There are, however, signs that hearts in DS without apparent structural heart defects also differ from those in the normal population. We aimed to compare the atrioventricular (AV) septum and valves in 3 groups: DS without AV septal defect (DS no-AVSD), DS with AVSD (DS AVSD) and control hearts. The ventricular septum, membranous septum and AV valves were examined and measured in histological sections of 15 DS no-AVSD, 8 DS AVSD and 34 control hearts. In addition, the ventricular septum length was measured on ultrasound images of fetal (6 DS AVSD, 9 controls) and infant (10 DS no-AVSD, 10 DS AVSD, 10 controls) hearts. The membranous septum was 3 times larger in DS no-AVSD fetuses compared to control fetuses, and valve dysplasia was frequently (64%) observed. The ventricular septum was shorter in patients with DS both with and without AVSD, as compared to the control group. DS no-AVSD hearts are not normal as they have a larger membranous septum, shorter ventricular septum and dysplasia of the AV valves as compared to control hearts. © 2015 S. Karger AG, Basel.
    No preview · Article · Jun 2015 · Fetal Diagnosis and Therapy
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    ABSTRACT: The differential insertion of the atrioventricular valves is the ultrasonographic representation of the more apical attachment of the tricuspid valve to the septum with respect to the mitral valve. A linear insertion is present when both valves form a linear continuum and is suggested as a marker for atrioventricular septal defects (AVSDs). The objective is to evaluate the anatomical substratum of differential and linear insertion of the atrioventricular valves in normal fetal hearts and fetal hearts with an AVSD. The extent and position of the fibrous skeleton and attachment of atrioventricular valves to the septum were studied in histological sections of 17 normal hearts and 4 hearts with an AVSD (10 + 0 weeks gestation - 3 days postpartum) with various immunohistochemical tissue markers. In addition, STIC volumes of 10 normal hearts and STIC volumes of 8 hearts with AVSD (13 + 6 - 35 + 5 weeks gestational age) were examined. The differential insertion of the atrioventricular valves was visible in normal hearts in the four-chamber plane immediately beneath the aorta. More towards the diaphragm, a linear insertion was found. In hearts with an AVSD, a linear appearance was observed in the four-chamber plane immediately beneath the aorta. Towards the diaphragm, however, first a differential and more caudal, a linear insertion was found. Both differential and linear insertion can be found in normal fetal hearts and fetal hearts with AVSD, dependent on the plane in which the four-chamber view is visualised. Therefore, measurement of the differential insertion is probably only useful in experienced hands.
    No preview · Article · Nov 2014 · Ultrasound in Obstetrics and Gynecology
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    ABSTRACT: The primary unseptated heart tube undergoes extensive remodeling including septation at the atrial, atrioventricular, ventricular, and ventriculo-arterial level. Alignment and fusion of the septal components is required to ensure full septation of the heart. Deficiencies lead to septal defects at various levels. Addition of myocardium and mesenchymal tissues from the second heart field (SHF) to the primary heart tube, as well as a population of neural crest cells, provides the necessary cellular players. Surprisingly, the study of the molecular background of these defects does not show a great diversity of responsible transcription factors and downstream gene pathways. Epigenetic modulation and mutations high up in several transcription factor pathways (e.g. NODAL and GATA4) may lead to defects at all levels. Disturbance of modulating pathways, involving primarily the SHF-derived cell populations and the genes expressed therein, results at the arterial pole (e.g. TBX1) in a spectrum of ventricular septal defects located at the level of the outflow tract. At the venous pole (e.g. TBX5), it can explain a variety of atrial septal defects. The various defects can occur as isolated anomalies or within families. In this review developmental, morphological, genetic, as well as epigenetic aspects of septal defects are discussed.
    No preview · Article · Oct 2014 · Annals of Medicine
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    ABSTRACT: During cardiogenesis the epicardium, covering the surface of the myocardial tube, has been ascribed several functions essential for normal heart development of vertebrates from lampreys to mammals. We investigated a novel function of the epicardium in ventricular development in species with partial and complete septation. These species include reptiles, birds and mammals. Adult turtles, lizards and snakes have a complex ventricle with three cava, partially separated by the horizontal and vertical septa. The crocodilians, birds and mammals with origins some 100 million years apart, however, have a left and right ventricle that are completely separated, being a clear example of convergent evolution. In specific embryonic stages these species show similarities in development, prompting us to investigate the mechanisms underlying epicardial involvement. The primitive ventricle of early embryos becomes septated by folding and fusion of the anterior ventricular wall, trapping epicardium in its core. This folding septum develops as the horizontal septum in reptiles and the anterior part of the interventricular septum in the other taxa. The mechanism of folding is confirmed using DiI tattoos of the ventricular surface. Trapping of epicardium-derived cells is studied by transplanting embryonic quail pro-epicardial organ into chicken hosts. The effect of decreased epicardium involvement is studied in knock-out mice, and pro-epicardium ablated chicken, resulting in diminished and even absent septum formation. Proper folding followed by diminished ventricular fusion may explain the deep interventricular cleft observed in elephants. The vertical septum, although indistinct in most reptiles except in crocodilians and pythonidsis apparently homologous to the inlet septum. Eventually the various septal components merge to form the completely septated heart. In our attempt to discover homologies between the various septum components we aim to elucidate the evolution and development of this part of the vertebrate heart as well as understand the etiology of septal defects in human congenital heart malformations.
    Full-text · Article · Sep 2014 · PLoS ONE
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    ABSTRACT: First trimester sonography is a widely used technique to examine the foetus early in pregnancy. The desire to recognise complex anatomy already in early developmental stages stresses the need for a thorough knowledge of basic developmental processes as well as recognition of cardiac compartments based on their morphology. In this paper, we describe the possibilities and limitations of sonographic assessment of the foetal heart between 10 and 14 weeks of gestation and correlate this to morphology. Examples of the most commonly detected congenital anomalies are atrioventricular septal defects, transposition of the great arteries, and hypoplastic left heart, which are shown in this paper.
    No preview · Article · Aug 2014 · Cardiology in the Young
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    ABSTRACT: Introduction: Bicuspid aortic valve (BAV) is common in Turner syndrome (TS). In adult TS, 82-95% of BAVs have fusion of the right and left coronary leaflets. Data in fetal stages are scarce. The purpose of this study was to gain insight into aortic valve morphology and associated cardiovascular abnormalities in a fetal TS cohort with adverse outcome early in development. Material and methods: We studied post-mortem heart specimens of 36 TS fetuses and 1 TS newborn. Results: BAV was present in 28 (76%) hearts. BAVs showed fusion of the right and left coronary leaflet (type 1 BAV) in 61%, and fusion of the right coronary and non-coronary leaflet (type 2 BAV) in 39%. There were no significant differences in occurrence of additional cardiovascular abnormalities between type 1 and type 2 BAV. However, all type 2 BAV hearts showed ascending aorta hypoplasia and tubular hypoplasia of the B segment, as opposed to only 55 and 64% of type 1 BAV hearts, respectively. Discussion: The proportion of type 2 BAV seems higher in TS fetuses than in adults. Fetal type 2 BAV hearts all had severe aortic pathology, possibly contributing to a worse prognosis of type 2 than type 1 BAV in TS.
    No preview · Article · Jun 2014 · Fetal Diagnosis and Therapy
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    ABSTRACT: Purpose: Bicuspid aortic valve (BAV) is the most common congenital heart defect. BAV leaflet orientation has prognostic significance in terms of valve disease, aortic dilatation and necessity for intervention. BAV is particularly common in Turner syndrome (TS). Ninety-five percent of BAVs in adult TS patients have anterior-posterior (AP) leaflet orientation, due to fusion of right- and left coronary leaflets. Data in fetal stages of TS are scarce. Available data indicate that a larger proportion of TS fetuses with BAV has left-right (LR) orientation of the leaflets (fusion of the right- or left coronary leaflet with the non-coronary leaflet). This might indicate a worse prognosis with a higher risk of fetal demise in LR BAV, possibly due to associated congenital heart disease. The purpose of our study was to gain insight in the morphology of the aortic valve and its associated cardiovascular malformations in fetal TS. Methods an results: We studied post-mortem heart specimens of 36 TS fetuses and 1 TS newborn. Abnormal aortic valve morphology was observed in 32 of 37 (86%) hearts: BAV in 28 (76%) hearts, unicommissural aortic valve in 2 (5%) hearts and aortic atresia in 2 (5%) hearts. In hearts with BAV, the leaflets showed AP orientation in 61% and LR orientation in 39% (Figure 1). There were no significant differences in occurrence of additional cardiovascular malformations between hearts with AP BAV or LR BAV. However, all hearts with LR BAV showed ascending aorta hypoplasia, as opposed to only 55% of hearts with AP BAV. In addition, all hearts with LR BAV had tubular hypoplasia of the aortic B-segment, as opposed to 64% of hearts with AP BAV. Conclusion: The large majority of TS fetuses shows abnormal aortic valve morphology. The proportion of LR BAV is higher in TS fetuses than reported in adults. Fetal TS hearts with LR BAV were all associated with severe pathology of the aorta, which may contribute to a worse prognosis of LR BAV in TS.
    Preview · Article · Aug 2013 · European Heart Journal
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    ABSTRACT: Heart development is a complex process during which the heart needs to transform from a single tube towards a fully septated heart with four chambers and a separated outflow tract. Several major events contribute to this process, that largely overlap in time. Abnormal heart development results in congenital heart disease, which has an estimated incidence of 1% of liveborn children. Eighty percent of cases of congenital heart disease are considered to have a multifactoral developmental background, whereas knowledge of monogenetic causes for congenital heart disease is still limited. This review focuses on several novel findings in cardiac development that might enhance our knowledge of aetiology and support refinement of prenatal diagnosis of congenital heart disease.
    No preview · Article · Jul 2013 · Seminars in Fetal and Neonatal Medicine
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    ABSTRACT: Understanding of cardiac outflow tract (OFT) remodeling is essential to explain repositioning of the aorta and pulmonary orifice. In wild type embryos (E9.5-14.5), second heart field contribution (SHF) to the OFT was studied using expression patterns of Islet 1, Nkx2.5, MLC-2a, WT-1, and 3D-reconstructions. Abnormal remodeling was studied in VEGF120/120 embryos. In wild type, Islet 1 and Nkx2.5 positive myocardial precursors formed an asymmetric elongated column almost exclusively at the pulmonary side of the OFT up to the pulmonary orifice. In VEGF120/120 embryos, the Nkx2.5-positive mesenchymal population was disorganized with a short extension along the pulmonary OFT. We postulate that normally the pulmonary trunk and orifice are pushed in a higher and more frontal position relative to the aortic orifice by asymmetric addition of SHF-myocardium. Deficient or disorganized right ventricular OFT expansion might explain cardiac malformations with abnormal position of the great arteries, such as double outlet right ventricle.
    Full-text · Article · Sep 2012 · Developmental Dynamics
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    ABSTRACT: The importance of the epicardium covering the heart and the intrapericardial part of the great arteries has reached a new summit. It has evolved as a major cellular component with impact both in development, disease and more recently also repair potential. The role of the epicardium in development, its differentiation from a proepicardial organ at the venous pole (vPEO) and the differentiation capacities of the vPEO initiating cardiac epicardium (cEP) into epicardium derived cells (EPDCs) have been extensively described in recent reviews on growth and transcription factor pathways. In short, the epicardium is the source of the interstitial, the annulus fibrosus and the adventitial fibroblasts, and differentiates into the coronary arterial smooth muscle cells. Furthermore, EPDCs induce growth of the compact myocardium and differentiation of the Purkinje fibers. This review includes an arterial pole located PEO (aPEO) that provides the epicardium covering the intrapericardial great vessels. In avian and mouse models disturbance of epicardial outgrowth and maturation leads to a broad spectrum of cardiac anomalies with main focus on non-compaction of the myocardium, deficient annulus fibrosis, valve malformations and coronary artery abnormalities. The discovery that in disease both arterial and cardiac epicardium can again differentiate into EPDCs and thus reactivate its embryonic program and potential has highly broadened the scope of research interest. This reactivation is seen after myocardial infarction and also in aneurysm formation of the ascending aorta. Use of EPDCs for cell therapy show their positive function in paracrine mediated repair processes which can be additive when combined with the cardiac progenitor stem cells that probably share the same embryonic origin with EPDCs. Research into the many cell-autonomous and cell-cell-based capacities of the adult epicardium will open up new realistic therapeutic avenues.
    No preview · Article · May 2012 · Differentiation
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    ABSTRACT: OBJECTIVES: Borderline left ventricle is the left ventricular morphology at the favorable end of the hypoplastic left heart syndrome. In contrast to the severe end, it is suitable for biventricular repair. Wondering whether it is possible to identify cases suitable for biventricular repair from a developmental viewpoint, we investigated the myocardial histology of borderline and severely hypoplastic left ventricles. METHODS: Postmortem specimens of neonatal, unoperated human hearts with severe hypoplastic left heart syndrome and borderline left ventricle were compared with normal specimens and hearts from patients with transposition of the great arteries. After tissue sampling of the lateral walls of both ventricles, immunohistochemical and immunofluorescence stainings against cardiac troponin I, N-cadherin, and connexin 43, important for proper cardiac differentiation, were done. RESULTS: All severely hypoplastic left hearts (7/7) and most borderline left ventricle hearts (4/6) showed reduced sarcomeric expressions of troponin I in left and right ventricles. N-cadherin and connexin 43 expressions were reduced in intercalated disks. The remaining borderline left ventricle hearts (2/6) were histologically closer to control hearts. CONCLUSIONS: Four of 6 borderline left ventricle hearts showed myocardial histopathology similar to the severely hypoplastic left hearts. The remainder were similar to normal hearts. Our results and knowledge regarding the role of epicardial-derived cells in myocardial differentiation lead us to postulate that an abnormal epicardial-myocardial interaction could explain the observed histopathology. Defining the histopathologic severity with preoperative myocardial biopsy samples of hearts with borderline left ventricle might provide a diagnostic tool for preoperative decision making.
    Full-text · Article · Mar 2012 · The Journal of thoracic and cardiovascular surgery
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    ABSTRACT: To study the clinical course and outcome of fetal sinus bradycardia (SB) due to maternal antibody-induced sinus node dysfunction. We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with elevated maternal anti-SSA/Ro and anti-SSB/La antibodies. Of the 6 cases diagnosed prenatally, 3 had isolated SB persisting after birth and had a good prognosis. Three fetuses with SB and severe myocardial involvement (congenital complete heart block and/or endocardial fibroelastosis) succumbed in utero in spite of treatment. Postmortem histopathology in 1 fetus showed inflammatory destruction of the sinus and atrioventricular nodes. SB was detected incidentally in a 7-year-old girl. She had intermittent heart block with progressive sinus arrest requiring permanent pacemaker. Fetal SB associated with maternal autoantibodies may persist in childhood, with a good prognosis in the absence of widespread cardiac involvement.
    Full-text · Article · Nov 2011 · The Journal of Rheumatology
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    ABSTRACT: The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.
    Full-text · Article · Nov 2011 · Developmental Dynamics
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    ABSTRACT: Increased nuchal translucency in the human fetus is associated with aneuploidy, structural malformations and several syndromes such as Noonan syndrome. In 60–70% of the Noonan syndrome cases, a gene mutation can be demonstrated. Previous research showed that aneuploid fetuses with increased nuchal translucency (NT) demonstrate an aberrant lymphatic endothelial differentiation. Fetuses with increased NT and normal karyotype (n = 7) were compared with euploid controls having normal NT (n = 5). A Noonan syndrome gene mutation was found in three out of seven fetuses with increased NT. Endothelial differentiation was evaluated by immunohistochemistry using lymphatic markers (PROX-1, Podoplanin, LYVE-1) and blood vessel markers vascular endothelial growth factor-A (VEGF-A), Neuropilin-1 (NP-1), Sonic hedgehog, von Willebrand factor, and the smooth muscle cell marker, smooth muscle actin. Nuchal edema and enlarged jugular lymphatic sacs (JLSs) were observed in fetuses with increased NT, together with abnormal lymphatic endothelial differentiation i.e. the presence of blood vessel characteristics, including high levels of VEGF-A and NP-1 expression. The enlarged JLSs contained erythrocytes and were surrounded by smooth muscle cells. This study shows an aberrant lymphatic endothelial differentiation in fetuses with increased NT and a normal karyotype (including Noonan syndrome fetuses), as was previously reported before in aneuploid fetuses.
    No preview · Article · Feb 2011 · Prenatal Diagnosis
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    ABSTRACT: A case of radiofrequency catheter ablation of atrioventricular (AV) nodal reentry tachycardia, in a patient with transposition of the great arteries after venous rerouting according to Mustard, is described. An electroanatomical map of the His and AV nodal region was created from inside the systemic venous atrium. Retrograde mapping of the pulmonary venous atrium was performed and the arterial catheter retracted to a position in close proximity to the venous catheter inside the intraatrial baffle. This position was chosen to deliver radiofrequency current. (PACE 2012; 35:e287-e290).
    Full-text · Article · Oct 2010 · Pacing and Clinical Electrophysiology
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    ABSTRACT: The purpose of this study was to evaluate ductus venosus flow velocities and a possible relationship with the type of cardiac defect in fetuses with increased nuchal translucency (NT). Seventy-two fetuses with normal NT and 137 fetuses with increased NT (>95th percentile) were evaluated. The ductus venosus pulsatility index for veins (PIV), late diastolic velocity (velocity during atrial contraction [a-V]), and intracardiac velocities were evaluated. In cases of pregnancy termination, a postmortem examination was performed. Cardiac defects were grouped into septal defects, left and right inflow obstruction, left and right outflow obstruction, and other defects. Data were evaluated by multilevel analysis. A cardiac defect was found in 45 fetuses with increased NT. Fetuses with increased NT showed a higher ductus venosus PIV and a lower a-V compared to fetuses with normal NT (P < .05). Within the group of fetuses with increased NT, a higher PIV and a lower a-V were found in cases with a cardiac defect compared to cases with a normal heart (P < .001). No differences in PIV and a-V were found between the types of cardiac defects. Intracardiac velocities showed no differences between fetuses with normal and increased NT, irrespective of the presence of a cardiac defect. Ductus venosus flow velocities in fetuses with increased NT are not related to a certain type of cardiac defect. This indicates that the altered ductus venosus flow velocities found in fetuses with increased NT cannot be explained by cardiac failure due to a specific altered cardiac anatomy.
    No preview · Article · Jul 2010 · Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine
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    ABSTRACT: We sought to assess blood flow in relation to jugular lymphatic distension in fetuses with increased and normal nuchal translucency (NT). In all, 72 fetuses with normal NT and 71 fetuses with NT >95th percentile were evaluated. NT size, jugular lymphatic sacs (JLS), jugular vein and ductus venosus pulsatility index for veins (PIV), and intracardiac velocities were measured. JLS were visualized in 22/72 fetuses with normal and in 55/71 fetuses with increased NT. Jugular vein and ductus venosus PIV was higher in fetuses with increased NT compared to normal NT (P < .01). Visibility of JLS was associated with a higher ductus venous PIV (P < .05), but not with a higher jugular vein PIV. Larger NT and larger JLS volumes were associated with higher jugular vein and ductus venosus PIV (P < .05). This study shows a relation among increased NT, jugular lymphatic distension, and altered blood flow in jugular vein and ductus venosus.
    Full-text · Article · Mar 2010 · American journal of obstetrics and gynecology

Publication Stats

1k Citations
263.51 Total Impact Points

Institutions

  • 1998-2015
    • Leiden University Medical Centre
      • • Department of Anatomy and Embryology
      • • Department of Cardiology
      Leyden, South Holland, Netherlands
  • 1983-2014
    • Leiden University
      • Institute of Biology Leiden
      Leyden, South Holland, Netherlands
  • 2012
    • Curium-LUMC
      Leyden, South Holland, Netherlands